布美诺肽可改善女性性功能障碍

好莱坞——据一项Ⅱb期临床试验的数据显示，存在性功能障碍的绝经前女性在家中自行皮下注射布美诺肽(bremelanotide)可显著提高性欲和性冲动，令人满意的性生活次数也会增加。

在由美国国立精神卫生研究所主办的一次新药临床评价小组会议上，弗吉尼亚大学精神病学和神经行为科学教授Anita H. Clayton博士指出，这种新型疗法对最常见的女性性功能障碍类型都有效，包括性欲低下以及性欲低下合并女性性唤起障碍患者。

Clayton博士解释道，女性性功能障碍其实非常常见，病因也是多方面的，往往令患者感到十分痛苦，而且目前尚未批准任何药物用于这类疾病的治疗，因此该领域的治疗需求远未得到满足。布美诺肽是一种环状7-氨基酸黑素皮质素肽，是α黑素细胞刺激素(α-MSH)的合成类似物，可以发挥黑素皮质素-4受体激动剂的功效。类似于α-MSH，布美诺肽可以对大脑内参与性反应的通路起到调节作用。

会上，Clayton博士报告了这项随机、双盲、多中心、Ⅱb期临床试验的结果。该试验总共纳入了327例符合性欲低下或者性欲低下合并女性性唤起障碍诊断标准的受试者。在接受了自行皮下注射的培训之后，所有受试者在家中按需自行注射单盲安慰剂共4周。然后，受试者被随机分组，接受安慰剂或布美诺肽0.75 mg、1.25 mg或1.75 mg(预充式注射器)的双盲治疗，也均为家中自行注射，共治疗12周。要求受试者在性生活前大约45分钟自行注射。每天最多只能注射1剂，4周内最多只能注射16剂。

该试验的主要终点是与注射安慰剂的28天基线期相比，12周双盲试验期的最后28天内令人满意的性生活次数的变化。研究者基于修订版女性性生活日记(FSEP-R)来评估令人满意的性生活次数。

结果显示，在注射安慰剂的对照组中令人满意的性生活次数平均增加了0.2次。布美诺肽0.75 mg组与对照组相比无显著改善。但布美诺肽1.25 mg组较之基线平均增加了0.7次，布美诺肽1.75 mg组平均增加了0.8次，与安慰剂对照组相比均显著改善，差异有统计学意义。

该试验也达到了次要终点，并且也呈现出剂量依赖性关系。安慰剂组女性性功能指数总分(一种经确证能反映总体性功能的指标)的平均变化为1.88分，布美诺肽1.25 mg和1.75 mg合并组的平均变化为3.6分，布美诺肽1.75 mg组为4.4分。

同样，从女性性生活苦恼量表-性欲/性唤起/性高潮(FSDS-DAO)总分(一种反映性功能障碍相关苦恼的指标)的平均改善情况来看，安慰剂组、布美诺肽1.25 mg和1.75 mg合并组、布美诺肽1.75 mg组的平均变化分别为-6.8分、-11.1分和-13.1分。

Clayton博士说，这些改善很有临床意义。值得一提的是，这些结局指标较之基线的平均变化在双盲治疗的第3、4个月仍然在持续增加。

还有一个令人鼓舞的结果是，布美诺肽组有相当高比例的患者的指标评分达到了提示性功能水平正常的阈值。例如，布美诺肽0.75 mg、1.25 mg和1.75 mg组分别有42.7%、45.5%和49%的患者的女性性功能指数总分＞26.5分，而安慰剂组仅36.5%。此外，安慰剂组有28.5%的患者FSDS-DAO总分＜18分，而布美诺肽0.75 mg、1.25 mg和1.75 mg组分别达到了40.5%、45.6%和47.5%。

而且，这种药物治疗的安全性较好，患者普遍耐受良好。布美诺肽组最常见的不良反应包括恶心、面潮红和头痛；发生率介于9%~24%，剂量越大则发生率越高；但这些事件大多为轻至中度。

Clayton博士报告称，布美诺肽组患者的血压平均升高了2 mmHg左右，大多只出现在给药后前4 h内。根据事先定义的血压变化标准而被迫退出试验的患者人数在安慰剂组和布美诺肽治疗组之间呈平均分布，这很让人安心。她指出，大约在5年前，一种布美诺肽鼻内制剂治疗男性勃起功能障碍和女性性功能障碍的研发项目就是因为明显的药物致高血压问题而被终止。而这项试验以及其他数据均提示，皮下给药不会导致高血压问题。

一项评估家中自行皮下注射布美诺肽治疗女性性功能障碍的决定性Ⅲ期临床试验预计将在今年晚些时候启动。

Clayton博士声明接受了布美诺肽开发商Palatin Technologies公司以及其他制药企业提供的研究经费和咨询费。

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By: BRUCE JANCIN, Internal Medicine News Digital Network

HOLLYWOOD, FLA. – Subcutaneous bremelanotide self-administered at home by premenopausal women with sexual dysfunction significantly boosted sexual arousal and desire and their number of satisfying sexual events, based on data from a phase IIb clinical trial.

The novel therapy proved effective both in women with hypoactive sexual desire disorder and in those with combined hypoactive sexual desire disorder/female sexual arousal disorder, among the most common forms of female sexual dysfunction, Dr. Anita H. Clayton noted at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

Female sexual dysfunction is distressing, very common, and multifactorial, and there is at present no approved pharmacotherapy for these disorders, according to Dr. Clayton, professor of psychiatry and neurobehavioral sciences at the University of Virginia, Charlottesville. Thus, this represents an area of significant unmet medical need, she said.

Bremelanotide is a cyclic 7-amino-acid melanocortin peptide. It is a synthetic analog of the hormone alpha-melanocyte–stimulating hormone (alpha-MSH). It functions as a melanocortin-4 receptor agonist. Bremelanotide, like alpha-MSH, is thought to modulate brain pathways involved in sexual response, Dr. Clayton explained.

She reported data from a phase IIb randomized, double-blind, multicenter trial involving 327 women who met diagnostic criteria for hypoactive sexual desire disorder or combined hypoactive sexual desire disorder/female sexual arousal disorder. After receiving instruction in self-administration of subcutaneous injections, all participants underwent 4 weeks of single-blind placebo self-dosing at home on an as-needed basis. Then they were randomized to 12 weeks of double-blind home treatment with placebo or bremelanotide at 0.75 mg, 1.25 mg, or 1.75 mg in prefilled syringes. Participants were instructed to inject themselves approximately 45 minutes prior to sexual activity. They were not to exceed 1 dose per day, or 16 doses in a 4-week period.

The primary endpoint was change between the numbers of satisfying sexual events during the 28-day baseline period on placebo and during the final 28 days of the 12-week double-blind study period, using the Female Sexual Encounter Profile-Revised.

The mean increase was 0.2 events in placebo-treated controls. Women randomized to 0.75 of bremelanotide didn’t fare significantly better than that.

However, women using bremelanotide at 1.25 mg had a mean 0.7-event increase from baseline, and those on 1.75 mg averaged a 0.8-event increase, both of which were significantly better than placebo.

Secondary endpoints were also positive, in dose-dependent fashion. The mean change over time in the Female Sexual Function Index total score, a validated measure of overall sexual functioning, was 1.88 for placebo, 3.6 in the pooled analysis of patients on bremelanotide at 1.25 or 1.75 mg, and 4.4 in those on 1.75 mg.

Similarly, the mean improvement on the FSDS-DAO (Female Sexual Distress Scale-Desire/Arousal/Orgasm) total score, an indicator of sexual dysfunction–related distress, was –6.8 for placebo, –11.1 for the pooled group on 1.25 or 1.75 mg of bremelanotide, and –13.1 for women on 1.75 mg.

These are clinically meaningful improvements, according to Dr. Clayton. Of note, the mean total score improvements, compared with baseline on these outcome measures, were still growing during the third and final month of double-blind treatment.

Also encouraging was the large percentage of women on bremelanotide whose scores reached thresholds indicative of normal levels of sexual function, she continued. For example, a Female Sexual Function Index total score greater than 26.5 was achieved in 42.7% of women on bremelanotide at 0.75 mg, 45.5% of those on 1.25 mg, and 49% on 1.75 mg, compared with 36.5% of placebo-treated controls. Moreover, a FSDS-DAO total score less than 18 was attained by 28.5% of women on placebo, 40.5% of those on bremelanotide at 0.75 mg, 45.6% on 1.25 mg, and 47.5% of those on 1.75 mg.

The drug therapy was safe and generally well tolerated. The most common bremelanotide-associated side effects were nausea, facial flushing, and headache, which affected 9%-24% of patients in dose-dependent fashion and were typically mild to moderate in nature.

Bremelanotide-treated patients averaged an increase in blood pressure of approximately 2 mm Hg, largely restricted to the first 4 hours after dosing. The number of patients forced to withdraw from the study based on predefined blood pressure change criteria was evenly distributed among the placebo and treatment groups, which was reassuring, Dr. Clayton said. Approximately 5 years ago, development of an intranasal formulation of bremelanotide for treatment of male erectile dysfunction as well as female sexual dysfunction was discontinued because of concerns about significant drug-induced hypertension. The current study, as well as other data, indicates that hypertension isn’t an issue with subcutaneous administration, she noted.

A definitive phase III clinical trial of at-home, self-administered subcutaneous bremelanotide for treatment of female sexual dysfunction is anticipated to start later this year.

Dr. Clayton reported receiving research support and consulting fees from Palatin Technologies, which is developing bremelanotide, as well as from other pharmaceutical companies.